The Association Study Of Calcyphosine (CAPS) Gene With Familial Febrile Seizures

Febrile convulsions, one of the most common epilepsy syndromes, occurin 2-6% of children before age 5 years. Although many studies have provedthat patients have a genetic predisposition to their development, the model ofinheritance is not known. Up to now, there have been many loci reported, suchas 8q13-21, 19p13.3, 2q23-24, 5q14-15 and so on. According to these newstudies, FS seems a complex disease with single major locus.How can we identify the susceptibility genes of FS from thesechromosomes regions? Firstly, according to the results of the Human GenomeProject, we rank all the functional genes in the susceptibility regions. Secondly,by examining the potential biological, etiological and pathological models ofFS, we select candidate genes for the association study.Our research panel previously carried out the linkage analysis inChinese pedigrees and the results suggested that the susceptibility genes mightbe located on the area of 19p13.3 between D19S593 and D19S395.Furthermore, using the accomplishments of the Human Genome Project, wefind that there are more than 40 functional genes and expressed sequence tagsdispersed in the locus, all of which are expressed in CES。In our study, we select calcyphosine(CAPS) gene as the candidate genecarrying out the association study. CAPS belongs to the superfamily ofproteins, containing 4 EF hand domains. Based on sequence similarities,CAPS is closed related to calmodulin. It firstly was cloned in the dog thyroid.In 1990 Lefort identified the location of human calcyphosine gene to the p13.3region of chromosome 19 by in situ hybridization. Following that, CAPS wastested expressing extensively in the rat brain, including the granule cells of thedentate gyrus of the hippocampus relative to the susceptibility of epilepsy.CAPS binds calcium and is regulated by cAMP, which making it playingimportant role in signal transmitting. Therefore we select CAPS gene as thecandidate gene. This gene contains 5 exons and encodes 189 amino acids.We firstly conducted PCR on the DNA from 30 children with familialfebrile seizures. The PCR products underwent sequencing to identify thepossible mutations. Secondly we genotyped 2 SNPs of CAPS gene in 54patients and 90 controls by the methods of PCR-RFLP. Our results show as thefollowing: (1)we couldn't find any mutation in the exons of CAPS gene.(2)the frequency of genotype of rs7249419 complied with the Hardy-Weinbergequilibrium. Neither genotype nor allele frequency showed a significantassociation with FS. (2) rs11437855 have only one genotype. These dataindicate that CAPS gene may not contribute to familial febrile seizures inchildren.CAPS is a novel protein cloned in nearly 20 years. The calcium-bindingproperty and phosphorylation characteristics of CAPS potentially allow it tointegrate signals originating from both calcium and camp cascades, whichcould constitute a privileged point of cross-signaling between these tworegulatory pathways in selected cell types. The pathogenesis of febrile seizures,as a epilepsy syndrome, may be similar to epilepsy. We know epilepsy genesmostly encode iron gates. So CAPS gene, as a protein encoding iron gatewhich affecting the excitability of the neurons, just is what we need to choose.In 1993, the neuronal localization of CAPS was tested by in situ hybridiza-...